We previously reported that deficiency of membrane-type five matrix metalloproteinase (MT5-MMP) prevents amyloid pathology in the cortex and hippocampus of 5xFAD mice, and ameliorates the functional outcome. We have now investigated whether the integrity of another important area affected in Alzheimer’s disease (AD), the frontal cortex, was also preserved upon MT5-MMP deficiency in 4-month old mice at prodromal stages of the pathology. We used the olfactory H-maze (OHM) to show that learning impairment associated with dysfunctions of the frontal cortex in 5xFAD was prevented in bigenic 5xFAD/MT5-MMP−/− mice. The latter exhibited concomitant drastic reductions of amyloid beta peptide (Aβ) assemblies (soluble, oligomeric and fibrillary) and its immediate precursor, C99. Simultaneously, astrocyte reactivity and tumor necrosis factor alpha (TNF-α) levels were also lowered. Moreover, MT5-MMP deficiency induced a decrease in N-terminal soluble fragments of amyloid precursor protein (APP), including soluble APPα (sAPPα), sAPPβ and the MT5-MMP-linked fragment of 95 kDa, sAPP95. However, the lack of MT5-MMP did not affect the activity of β- and γ-secretases. In cultured HEKswe cells, transiently expressed MT5-MMP localized to early endosomes and increased the content of APP and Aβ40 in these organelles, as well as Aβ levels in cell supernatants. This is the first evidence that the pro-amyloidogenic features of MT5-MMP lie, at least in part, on the ability of the proteinase to promote trafficking into one of the amyloidogenic subcellular loci. Together, our data further support the pathogenic role of MT5-MMP in AD and that its inhibition improves the functional and pathological outcomes, in this case in the frontal cortex. These data also support the idea that MT5-MMP could become a novel therapeutic target in AD.
We previously demonstrated that membrane type 1 (MT1) matrix metalloproteinase (MMP) was up‐regulated in the hippocampus of the model of transgenic mice bearing 5 familial mutations on human amyloid precursor protein (APP) and presenilin 1 of Alzheimer disease (AD), and that the proteinase increased the levels of amyloid β peptide (Aβ) and its APP C‐terminal fragment of 99 aa in a heterologous cell system. Here we provide further evidence that MT1‐MMP interacts with APP and promotes amyloidogenesis in a proteolytic‐dependent manner in Swedish APP‐expressing human embryonic kidney 293 (HEKswe) cells. MT1‐MMP–mediated processing of APP releases a soluble APP fragment, sAPP95. This process partly requires the activation of endogenous MMP‐2 but is independent of β‐site APP cleaving enzyme 1 (BACE‐1) or α‐secretase activities. In contrast, MT1‐MMP–mediated increase of Aβ levels involved BACE‐1 activity and was inhibited by tissue inhibitor of MMP‐2, a natural inhibitor of both MT1‐MMP and MMP‐2. Interestingly, near abolishment of basal Aβ production upon BACE‐1 inhibition was rescued by MT1‐MMP, indicating that the latter could mimic β‐secretase–like activity. Moreover, MT1‐MMP promoted APP/Aβ localization in endosomes, where Aβ production mainly occurs. These data unveil new mechanistic insights to support the proamyloidogenic role of MT1‐MMP based on APP processing and trafficking, and reinforce the idea that this proteinase may become a new potential therapeutic target in AD.—Paumier, J.‐M., Py, N. A., González, L. G., Bernard, A., Stephan, D., Louis, L., Checler, F., Khrestchatisky, M., Baranger, K., Rivera, S. Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP‐2 and BACE‐1 activities, and the modulation of APP trafficking. FASEB J. 33, 2910–2927 (2019). http://www.fasebj.org
We previously discovered the implication of membrane‐type 5‐matrix metalloproteinase (MT5‐MMP) in Alzheimer's disease (AD) pathogenesis. Here, we shed new light on pathogenic mechanisms by which MT5‐MMP controls the processing of amyloid precursor protein (APP) and the fate of amyloid beta peptide (Aβ) as well as its precursor C99, and C83. We found in human embryonic kidney cells (HEK) carrying the APP Swedish familial mutation (HEKswe) that deleting the C‐terminal non‐catalytic domains of MT5‐MMP hampered its ability to process APP and release the soluble 95 kDa form (sAPP95). Catalytically inactive MT5‐MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endolysosomal system, likely through interactions of the proteinase C‐terminal portion with C99. Most interestingly, the deletion of the C‐terminal domain of MT5‐MMP caused a strong degradation of C99 by the proteasome and prevented Aβ accumulation. These discoveries reveal new control of MT5‐MMP over APP by proteolytic and non‐proteolytic mechanisms driven by the C‐terminal domains of the proteinase. The targeting of these non‐catalytic domains of MT5‐MMP could, therefore, provide new insights into the therapeutic regulation of APP‐related pathology in AD.
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